SRP287618 PRJNA669828 GSE159596 Non-coding RNAs shape cortical neurons developmental trajectories A hallmark of cortical evolution is the high dynamic subventricular zone (SVZ) expansion, where basal progenitors (BPs) amplify and neuronal transcriptional programs unfold. How non-coding molecular factors such as microRNAs influence these developmental trajectories and regulate the acquisition of cortical type identities is largely unknown. Here we demonstrate that miR-137 and miR-122 regulate the positioning and identity features of superficial layer cortical neurons by acting at distinct steps of their developmental trajectories. MiR-137 sustains basal progenitor amplification by reverting their neurogenic commitment and inducing high proliferative state upregulating Cd63 and inhibiting Myt1l. Cd63 is an extra-cellular matrix (ECM) receptor which interacts with ??b3- and ?1-integrin pathways to promote proliferation, while Myt1l is a transcription factor that promotes and sustains neuronal fate. The BPs amplification by miR-137 is converted in the promotion of intracortical projecting neuron (ICPN) identity and L2/3 expansion. As opposed to miR-137, miR-122 acts postmitotically, affecting the bioelectrical properties, the calcium and cytoskeleton dynamics of newborn neurons as well as their transcriptional program, leading to a persistent molecular immaturity across time. Overall, these findings reveal that miR-137 and miR-122 are key regulators of the developmental trajectory of cortical neurons across evolution. Overall design: Investigation of the non-coding RNAs miR-122 and miR-137 overexpression on progenitor and neuron transcriptional programs. psil-miR122, psil-miR137 or psil-scramble (control) plasmids were in utero electroporated together with pUB-GFP or pUB-Tomato plasmid in mouse embryos at embryonic day (E) 14.5, and cells collected at E15.5, E17.5 or postnatal day (P) 7 using fluorescence activated cell sorting (FACS). For comparison with layer 4 and layer 2/3 control cell molecular identities, pUB-GFP/Tomato plasmid was in utero electroporated at E14 and E15.5 respectively and cells collected at P3 and P7 using FACS. Collected cells were then processed for single-cell transcriptomics. psil-miR122 was in utero electroporated together with pUB-GFP plasmid in mouse embryos at E14.5; superficial and deep layers were microdissected at P7 and cells collected using FACS before being processed for bulk RNA sequencing. GSE159596 pubmed 35172154